Hyperechogenicity of substantia nigra in Parkinson's disease – Searching for genetic predictors

In spite of extensive research the cause of Parkinson's disease, the second most common neurodegenerative disorder, is still unclear. Several genes have been indentified in the last years to be related to the pathogenesis of PD, and a complex interplay between genes, environment and aging has been suggested. However, these genes are only associated with a minority of PD cases and the exact gene – environment interaction still remains to be elucidated.

Using transcranial sonography (TCS) the specific echofeature „hyperechogenicity of the substantia nigra (SN)“ may be visualized in more than 90% of patients with idiopathic PD in comparison to only 9% of healthy adults. Several studies indicate that signal intensity of the SN is related to tissue iron levels. Moreover, studies in relatives of PD patients indicate inheritance of the ultrasound signal. Therefore, it seems to be reasonable to investigate genes involved in brain iron metabolism in PD patients with SN hyperechogenicity.

Here, we screened the heme oxygenase-1 gene (HO-1), which plays an important role in brain-iron metabolism for single nucleotide polymorphisms (SNPs). This key enzyme in heme catabolism functions also as an antioxidant enzyme. We performed SNaPshot analyzes (ABI PRISM®, Applied Biosystems) of 300 PD patients with hyperechogenicity of SN in comparison to 300 matched healthy controls. In addition, we investigated (GT)n repeat lengths polymorphisms in the promoter region of this gene.

As normally iron does not enter the brain except via certain transport proteins, we investigated a second gene, which is very important for the blood-brain barrier, the so called multidrug resistance gene 1 (MDR1) for SNPs possibly associated with PD and hyperechogenicity of the SN.

In 5 SNPs of the mentioned genes investigated so far, no association with PD and SN hyperechogenicity was found.

As not sequence variations in genes but expression levels of proteins may be causative for disease manifestation we are currently investigating expression profiles of the peripheral blood of PD patients with SN hyperechogenicity and matched healthy controls without SN hyperechogenicity with microarray technology (GeneChip®Humane Genome U133 Plus 2.0 Array, Affymetrix). First analyses indicate group differences also in proteins involved in brain iron metabolism.